The 9th International Forum on Stem Cells (IFSC) in 2024 focuses on basic stem cell research, regenerative medicine, cell therapy, and the application of clinical research guidelines, gathering experts and scholars from around the world to discuss the latest frontiers of scientific discoveries and technological advancements. During the conference, "Hematology Frontier" specially invited Dr. Simón Méndez-Ferrer from the Cambridge Stem Cell Institute to share key pathways for improving the treatment of myeloid malignant tumors from the perspective of microenvironmental regulation.

Hematology Frontier：Myeloid malignancies are clonal disorders of the progenitor cells or hematopoietic stem cells. Could you discuss how cells in the bone marrow microenvironment influence the progression of these diseases and how we can use this knowledge to improve treatment strategies?

Dr. Simón Méndez-Ferrer：So actually, it was quite striking when people started examining the possibility that the cells that are not the mutant cells responsible for hematological diseases, but rather, the microenvironmental cells, might play a role in generating alterations in non-hematopoietic cells. These alterations were of different types, expressing molecules that were mutated in the case of germline mutations during hematological malignancies. But in other cases, they simply represented alterations in non-hematopoietic cells. And it was striking that in most of these experiments, the mouse models developed a type of disease that resembled myeloproliferative neoplasms. This suggests an important role for non-hematopoietic cells in the development of these diseases. This observation was made many years ago. Subsequently, researchers began to investigate which cells might be more important compared to others and found evidence that the niche could be an oncogenic inducer for the development of these malignancies.

However, most of the evidence for the role of the microenvironment actually stems from the consequences of mutations in hematopoietic cells, whereby the microenvironment becomes altered and stops functioning properly to support hematopoiesis, instead promoting the development of malignancy.

The alteration of the microenvironment can develop over many years. Some of these mutations are now detectable even before birth. Yet, patients typically manifest the disease associated with aging. Clearly, many factors are involved in the overall environment over the years that may contribute to the onset and progression of the disease. Therefore, now that this disease can be detected quite early, there is an opportunity for intervention and prevention of damage to the microenvironment, which may impede disease progression or enhance treatment effectiveness once the disease has developed.

Hematology Frontier：Your team at the University of Cambridge is researching how to improve the treatment of myeloid malignancies by modulating the microenvironment. What key findings in your research could provide clues for developing new treatment strategies?

Dr. Simón Méndez-Ferrer：So the most interesting findings suggest that the niche has limited capacity to control the expansion of the mutant clone that is driving these diseases.And actually, we found that in disorders such as myeloproliferative neoplasm, where there is a variety of manifestations and with different levels of disease expansion or mutant clone expansion, leading to a transformation into a more dangerous situation for the patient.This heterogeneity is also related to the different interactions with particular microenvironments. We have identified certain molecules that are involved in these interactions, and we think we could target those to restore the normal interactions of hematopoietic stem cells with their niche and prevent the abnormal detachment from a niche that effectively controls stem cell expansion. Instead, they relocate to a permissive environment where the mutant clone can expand more freely. So I think that’s an exciting opportunity for intervention, potentially complementing the actual targeting of the mutant clone.

Hematology Frontier：How do you view the potential of immunotherapy and targeted therapy in the treatment of myeloid malignancies, especially considering microenvironmental regulation? Are there specific cell types or strategies that show particular promise in your research?

Dr. Simón Méndez-Ferrer：There is a revival in the research around the microenvironment. This is also encompassing the immune microenvironment that has been studied mostly in the context of solid tumors.But now there is a huge interest also in the immune microenvironment for hematopoietic cells, because it is clear that these immune mechanisms are also modified through interaction with the microenvironment. When you come up with an immunotherapy, you need to make sure that you don’t encounter an immune-suppressive microenvironment that will hinder the effectiveness of the treatment. Cells should work as efficiently as expected. Also, there is interesting regulation through the macrophages that are involved in the clearance of mutant cells. Not only the adaptive immune system, but also the innate immune system is very important in this context. And the microenvironment, depending on whether it is immunosuppressive or stimulatory, may participate in the response to this immunotherapy. So I think this is an important area.